Fetal Alcohol Syndrome (FAS) is the leading cause of preventable cognitive impairment in the U.S. because drinking during pregnancy continues despite numerous educational programs. Estimates of the total lifetime cost of caring for a child with FAS can range from $860,000 to $4.2 million. Contributing to this cost is health care, special education, psychotherapy / counseling, welfare, and crime / justice system. To date, there are no effective pharmaceutical interventions to prevent or reduce the suffering of these children. The ultimate objective of the PI is to rationally identify and test therapies that could protect developing neurocircuits or reverse ethanol-induced damage thus preserving cognitive function in children at significant risk for injury. The immediate goal of this project is to deterine if varenicline is an effective intervention for reversing the effects of perinatal ethanol exposure Although there has been much interest in the promise of neurotrophic agents, neuroactive peptides, dietary antioxidant or choline supplements, and NMDA receptor antagonists, these agents have yet to lead to an effective, FDA approved treatment for FAS / FASD. We propose to test a novel therapeutic and the central hypothesis that: the FDA approved smoking cessation agent, varenicline, will ameliorate the long-term, negative effects of 3rd trimester ethanol-induced distortions of critically- timed events in neural development and cognitive function. The rationale for the proposed research is based upon positive results from studies suggesting varenicline reduces ethanol consumption and reverses ethanol-induced learning deficits as well as preliminary data from our lab suggesting varenicline ameliorates ethanol-induced GABA and learning deficits. To test this hypothesis, we propose three specific aims: Aim 1 will use a human 3rd trimester equivalent model of ethanol-induced brain damage, electrophysiology, and RT-PCR techniques to determine whether varenicline reverses ethanol-induced disruptions of critically-timed events in GABAergic synaptic development. Aim 2 will use electrophysiology, calcium-sensitive fluorescent imaging, and single-cell RT-PCR in an acutely dissociated neuronal preparation to determine if 3rd trimester equivalent ethanol exposure disrupts the maturation of GABAARs from depolarizing to hyperpolaring Cl- channels and if varenicline reverses ethanol's impact by facilitating this aspect of GABAAR maturation. Aim 3 will determine whether varenicline ameliorates ethanol-induced learning deficits in the Morris water maze in our human 3rd trimester equivalent model of FASD. This work is significant because it will test a therapy for FASD, the leading cause of cognitive impairment in the U.S., as well as determine if varenicline itself has adverse effects on GABA development and cognition. The experimental approach is innovative because this translational research proposal focuses on assessing the effectiveness of a smoking cessation agent as a novel therapeutic for FASDs using a multidisciplinary approach and an established ethanol exposure model.